The 2-alkyl-3-aroylbenzofuran derivatives of Formula I,
wherein R is lower alkyl and Ar is a substituted phenyl, are well known antiarrhythmic drugs. Two representative molecules, N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)methanesulfonamide—compound (1) and (2-butylbenzofuran-3-yl)(4-(2-(diethylamino) ethoxy)-3,5-diiodophenyl)methanone—compound (2) are currently active pharmaceutical ingredients on the market. The compound (1) is a recent enhancement versus compound (2) used for treatment of atrial fibrillation since decades.

A basic approach to prepare 3-aroylbenzofuran derivatives includes Friedel-Crafts reaction of anisoyl chloride to benzofuran or 5-nitrobenzofuran ring, demethylation of methoxy group and side chain coupling (U.S. Pat. No. 3,248,401, EP 0425359, EP 0471609—Scheme 1). Harsh conditions of Friedel-Crafts reaction and demethylation are less suitable for routine industrial production. In a special case of preparation of 5-amino substituted derivatives at least two steps are needed for preparation of starting 2-butyl-5-nitrobenzofuran and two steps for conversion of nitro group, so the number of steps is increased to at least seven.

Similar, but more convergent approach is described in WO 02/048132 (Scheme 2).

The patent application WO 05/066149 describes a reverse Friedel-Crafts reaction, but the main drawback of this approach is formation of byproducts arising from concurrent ortho substitution due to limited regioselectivity (Scheme 3).

More recent approaches (WO 09/044,143, WO 10/038,029, WO 10/040,261) avoid Friedel-Crafts coupling and apply an oxa variation of the Fischer indole synthesis (Scheme 4)

All of these synthetic procedures of 3-aroyl-5-aminobenzofuran derivatives started from nitro derivatives and the active molecule is finally converted to a pharmaceutically applicable form, which is often a pharmaceutically acceptable salt. It was surprisingly found that the preparation of salts of N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)methanesulfonamide from base is poorly reproducible, in most cases oils and foams were obtained. Time consuming additional efforts on purification of base have to be done in order to perform smooth preparation of solid N-(2-butyl-3-(4-(3-(dibutylamino)propoxy) benzoyl)benzofuran-5-yl)methanesulfonamide hydrochloride. Most of impurities originate in reduction of nitro group which proceeds via reactive nitroso, hydroxyamino and diazo intermediates that may produce several byproducts. It would be favorable to find better reduction conditions or to move the reduction step to earlier steps of the synthesis. The best solution would be to avoid nitro group all together. The nitro group is one of potential genotoxicity causing moieties in the molecule, so a handling of nitro compounds needs special measures in a production line.
The application WO 02/048132 describes a synthetic route wherein reduction of the nitro group is performed in earlier steps (Scheme 5), however, the preparation still needs the use of expensive catalysts and Friedel-Crafts conditions.

Another approach from the patent literature (WO 03/040120) avoids use of nitro intermediates but the procedure via alternative protection of amino group suffers from numerous steps.
There is still need for a short and efficient synthesis of 3-aroyl-5-aminobenzofuran derivatives. The invention satisfies this need.